Autoimmune hepatitis

Abstract

Autoimmune hepatitis (AIH) is a rare disease, characterized by female predominance, hypergammaglobulinemia, autoantibodies, association with HLA DR3 and HLA DR4 and a good response to immunosuppression. Different subtypes of AIH may be distinguished, based on differences in the autoantibody patterns. AIH type 1 is characterized by anti-nuclear (ANA) and/or anti-smooth muscular (SMA) autoantibodies. AIH type 2 is characterized by liver/kidney microsomal autoantibodies (LKM). AIH type 3 may be distinguished by autoantibodies to soluble liver proteins (SLA) or the liver pancreas antigen (LP). AIH-2 affects predominantly pediatric patients and is characterized by a more severe clinical course, a higher frequency of relapse under immunosuppressive treatment and a more frequent progression to cirrhosis. In contrast, AIH types 1 and 3 show a higher age of onset and a better long-term response to immunosuppressive treatment. At present, the treatment of choice is prednisone alone or a combination with prednisone and azathioprine. Both treatment protocols show high survival rates. However, a rate of 13% of treatment failures and the failure to induce permanent remission in most patients underlines the urgent need to develop additional treatment regimens. A yet unknown genetic predisposition is believed to act as the underlying etiological factor in AIH. This genetic predisposition includes a few known risk factors such as the presence of HLA DR3 or HLA DR4, deletions of C4A alleles and female gender. Furthermore, it has to be postulated that defects in immunoregulatory genes exist. A model for such defects may be the autoimmune polyglandular syndrome type 1 (APS1), which results from the defects in a single gene, the autoimmune regulator type 1 (AIRE-1). Patients with APS1 suffer from mucocutaneous candidiasis and a number of organ-specific autoimmune diseases. Characteristic is a high variability in the number and character of the disease components in APS1, indicating that other genetic and environmental factors may strongly modulate the outcome of disease. Environmental factors may comprise chemical influences, such as nutritional compounds and drugs, or virus infections. Several drugs or chemicals were shown to induce hepatitis with autoimmune involvement, e.g. tienilic acid, dihydralazine and halothane. Adduct formation of an activated metabolite is believed to act as a trigger and to induce a specific immune response. Similarly, viruses were repeatedly shown to trigger autoimmune hepatitis. In virus infections, sequence similarities between viral and self-proteins may trigger autoimmune processes and the simultaneous presence of inflammatory cytokines during virus infection may further increase the risk of developing self-perpetuating autoimmune reactions which overshoot.

Molecular Mimicry and Primary Biliary Cirrhosis: Premises Not Promises

“…39 Several drugs or chemicals have been shown to induce hepatitis with autoimmune involvement, e.g., tienilic acid, dihydralazine, and halothane. 40 The most intimately associated xenobiotic-induced liver disease associated with PBC, halothane hepatitis, occurs when susceptible patients mount an immune response to trifluoroacetylated protein antigens, formed following cytochrome P450 -mediated bioactivation of halothane to trifluoroacetyl chloride. 41 Exposure to trifluoroacetyl acid (TFA)-conjugated self proteins, both in humans and experimental animals, has led to antibody responses against such TFA-self proteins.…”

A novel IgM class autoantibody to a hepatocyte-related 190 kDa molecule in patients with type 1 autoimmune hepatitis

“…[1][2][3] Studies of LSP revealed that antibody to the asialoglycoprotein receptor was a specific marker of AIH. 4,5 In addition, recent evidence indicates that there may be several autoantibodies that recognize hepatocyte-associated molecules.…”

Remission with ursodeoxycholic acid of type 1 autoimmune hepatitis resistant to azathioprine and steroids

“…This was also our patient's phenotype. In Czaja's study a high proportion of patients were HLA-DR17, which is associated with poorer outcome (23)(24)(25). (27).…”